Povetacicept reduces disease activity in MG mouse model
Treatment lowers disease-causing antibody levels, study finds
Povetacicept, a treatment for autoimmune diseases in the pipeline of Vertex Pharmaceuticals, reduced disease activity in a study with a mouse model of myasthenia gravis (MG) by lowering the levels of disease-causing antibodies in the bloodstream.
Researchers also observed that povetacicept outperformed efgartigimod — approved as Vyvgart and Vyvgart Hytrulo for treating generalized MG — as well as another experimental medication called telitacicept.
“Povetacicept may therefore confer beneficial clinical outcomes in the treatment of MG,” they wrote.
The study, “Povetacicept (ALPN-303; TACI vTD-Fc), an enhanced, potent dual inhibitor of BAFF and APRIL, ameliorates experimental autoimmune myasthenia gravis in C57BL/6N mice,” was published in Frontiers in Immunology. It was funded in part by Alpine Immune Sciences, which was developing povetacicept before being acquired by Vertex last year.
Immune B-cells normally produce antibodies to help the body fight infection. In MG, they also produce self-reactive antibodies that bind to proteins such as the acetylcholine receptor (AChR) on muscle cells, preventing them from receiving signals from nerve cells. This leads to MG symptoms such as muscle weakness and fatigue.
Fusion protein
Povetacicept, also known as ALPN-303, is a fusion protein, meaning it combines parts of different proteins into a new one. It is designed to simultaneously block BAFF and APRIL, two proteins that help B-cells survive and activate to produce antibodies, including those that cause autoimmune diseases such as MG.
Earlier preclinical data from Alpine showed that povetacicept outperformed efgartigimod and off-label rituximab (marketed as Rituxan, with biosimilars available) in reducing disease activity in a mouse model of MG. Efgartigimod works by increasing the rate at which antibodies are broken down, while rituximab depletes B-cells by targeting a protein called CD20 on their surface.
More data were provided in the study, in which mice received either povetacicept, telitacicept, efgartigimod, an anti-CD20 antibody (similar to rituximab), or a placebo. All were given twice weekly, except the anti-CD20 antibody, which was given once weekly. Like povetacicept, telitacicept blocks APRIL as well as another B cell-stimulating protein called BLyS.
Disease activity was evaluated using the experimental autoimmune myasthenia gravis (EAMG) clinical scale, in which higher scores indicate more severe symptoms. At the start of treatment, all groups of mice had similar clinical scores and antibody levels.
Povetacicept reduced disease activity in the mouse model of MG, whether treatment began at the earliest symptoms of the disease (week 7) or two weeks later, when symptoms had worsened. At the final assessment, both groups had significantly lower scores than mice given the placebo.
Both povetacicept and telitacicept led to milder disease activity at week 13 (the end of the experiment), with average clinical scores of 0.67 and 0.83, compared with 1.9 in mice given the placebo.
Only povetacicept significantly reduced levels of anti-AChR antibodies in circulation and increased AChR levels in muscle tissue.
“Treatment with povetacicept reduced clinical manifestation of disease in the EAMG mouse model, which was associated with a significantly lower level of anti-AChR [blood] antibodies and higher content of muscle AChR,” the researchers wrote.
Povetacicept also reduced the number of B-cells and their proliferation in lymph nodes. These small structures filter and organize immune cells, helping to regulate the immune response. Telitacicept had similar but weaker effects.
The proportion of other immune cells called T-cells was significantly higher in mice treated with povetacicept compared with those on telitacicept or the placebo. This increase likely reflected a relative shift due to the reduction of B-cells, the scientists noted.
Similar to povetacicept, efgartigimod significantly reduced disease activity compared with the placebo. However, efgartigimod did not reduce levels of anti-AChR antibodies. The anti-CD20 antibody reduced the number of B-cells and the levels of anti-AChR antibodies but had no significant effects on clinical scores.
“These data suggest that povetacicept may represent an effective and innovative molecule to treat MG and support its evaluation in future clinical trials,” the researchers wrote, adding that povetacicept may have “comparable or better efficacy than clinically relevant therapeutics.”
Povetacicept is in Phase 3 clinical testing for IgA nephropathy, an autoimmune disease that damages the kidneys. Two ongoing Phase 1/2 clinical trials are also testing it for autoimmune cytopenia (low numbers of blood cells) and autoantibody-associated glomerular disease, including IgA nephropathy.
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